MIT chemists automate production of synthetic complex carbohydrates

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CAMBRIDGE, Mass. -- When scientists were finally able to create synthetic proteins and nucleic acids in the laboratory, modern-day miracles such as gene sequencing and DNA chips quickly followed.

But synthesizing these was child's play compared with the third category of biopolymers known as carbohydrates, or sugars. MIT researchers report in the Feb. 2 online edition of Science that they have automated the production of these extremely complex molecules for the first time. In so doing, they have opened the door to a flood of potential new research and disease treatments.

"We have developed a tool that cuts the time required to make an oligosaccharide (molecules made up of several simple sugar groups joined in a chain) by a factor of 100," said Peter H. Seeberger, Firmenich Assistant Professor of Chemistry at MIT and the paper's main author.

For the first time, biologically significant structures -- ones that are involved in cancers and a whole host of diseases -- will be readily available for any researcher to probe, analyze and manipulate. Researchers for the first time will be able to design and synthesize large numbers of different sugars and test their effect on cells.

COMPLEX BUILDING BLOCKS

Carbohydrates come in so many three-dimensional shapes and connect to each other in so many ways, building even a simple oligosaccharide could involve an astronomical number of possible construction combinations. The difference in complexity between building a protein and building a sugar is akin to stringing beads vs. constructing a 3-D scale model of Notre Dame.

Sugars are so difficult for biologists to purify and chemists to synthesize that researchers have been largely unable to study them closely in the body. "People have not gotten their hands on a good quantity of 'clean' carbohydrates" to study, Seeberger says.

That is about to change. Seeberger and MIT graduate students Obadiah J. Plante and Emma R. Palmacci have taken a commercially available peptide synthesizer (they got a used one relatively cheap) and modified it to mix, wash and cool a series of sugar-based reagents.

Following a simple sequence of steps that ensure that the sugar bonds form as desired, the substance ends up in a small glass cylinder that bubbles and shakes like a witch's cauldron at regular intervals while it produces the exact right chain of molecules.

In about 18 hours, the tabletop machine made a complex chain of 12 sugar units, which would have taken around three months to accomplish by hand.

HELPING CELLS INTERACT

While carbohydrates have a number of functions, including energy storage and metabolism, to Seeberger, their apparent use as a bioreceptor in cell-to-cell communication is their most exciting function.

When two cells come together, it is often the loosely attached carbohydrate protruding from one that interacts with the protein onthe other. The carbohydrate moderates the interaction -- whether beneficial or lethal -- between the two.

The challenging sugar structures that Seeberger's group is attempting to create with the machine are those involved in tropical diseases, cancer, HIV and infectious diseases.

If researchers knew what role a specific carbohydrate played in a disease, they might be able to design a drug that either enhanced or halted that role.

SUGARS ON DEMAND

The long-term goal, Seeberger says, is for a biologist or biochemist to be able to buy some monomers (the building blocks of a chain of sugar molecules), and program a machine that spits out the carbohydrate of choice.

While that reality is probably five to 10 years away, within six months researchers will be able to call in an order for a carbohydrate to Plante, one of the authors of the Science paper, who is starting a company to do just that.

"Once the chemistry works, the automation is easy," says Seeberger, who is now tackling synthesis of the last and most difficult holdouts: sialac acid containing oligosaccharides and heparin-like glycosaminoglycans. "The ease of acquiring defined structures from a machine will impact the field of glycobiology such that we may one day be able to fully appreciate the importance of oligosaccharides and glycoconjugates in nature."

This work is supported by the Mizutani Foundation for Glycoscience and the Petroleum Research Fund of the American Chemical Society. Obadiah Plante was supported by a graduate fellowship from the Division of Organic Chemistry of the American Chemical Society, sponsored by Pfizer Inc., and Emma Palmacci received a graduate fellowship from Merck.